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BACKGROUND AND OBJECTIVES: Autoimmune nodopathies with antibodies against the paranodal proteins show a distinct phenotype of a severe sensorimotor neuropathy. In some patients, complete remission can be achieved after treatment with rituximab whereas others show a chronic course. For optimal planning of treatment, predicting the course of disease and therapeutic response is crucial. METHODS: We stimulated peripheral blood mononuclear cells in vitro to find out whether secretion of specific autoantibodies may be a predictor of the course of disease and response to rituximab. RESULTS: Three patterns could be identified: In most patients with anti-Neurofascin-155-, anti-Contactin-1-, and anti-Caspr1-IgG4 autoantibodies, in vitro production of autoantibodies was detected, indicating autoantigen-specific memory B cells and short-lived plasma cells/plasmablasts as the major source of autoantibodies. These patients generally showed a good response to rituximab. In a subgroup of patients with anti-Neurofascin-155-IgG4 autoantibodies and insufficient response to rituximab, no in vitro autoantibody production was found despite high serum titers, indicating autoantibody secretion by long-lived plasma cells outside the peripheral blood. In the patients with anti-pan-Neurofascin autoantibodies-all with a monophasic course of disease-no in vitro autoantibody production could be measured, suggesting a lack of autoantigen-specific memory B cells. In some of them, autoantibody production by unstimulated cells was detectable, presumably corresponding to high amounts of autoantigen-specific plasmablasts-well in line with a severe but monophasic course of disease. DISCUSSION: Our data suggest that different B-cell responses may occur in autoimmune nodopathies and may serve as markers of courses of disease and response to rituximab.
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Autoanticuerpos , Leucocitos Mononucleares , Rituximab , Humanos , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Femenino , Masculino , Adulto , Leucocitos Mononucleares/inmunología , Rituximab/farmacología , Persona de Mediana Edad , Factores de Crecimiento Nervioso/inmunología , Adulto Joven , Contactina 1/inmunología , Anciano , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/tratamiento farmacológico , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Adolescente , Moléculas de Adhesión Celular/inmunologíaRESUMEN
In recent years, immunotherapy has emerged as a crucial component of cancer treatment. However, its efficacy remains limited across various cancer types, highlighting unmet needs. Poliovirus receptor-related 2 (PVRL2) and Poliovirus receptor (PVR) are members of the Nectin and Nectin-like Molecules family, known for their role as cell-cell adhesion molecules. With the development of immunotherapy, their involvement in tumor immune mechanisms as immune checkpoint factors has garnered significant attention. PVRL2 and PVR are predominantly expressed on tumor cells and antigen-presenting cells, binding to PVRIG and TIGIT, respectively, which are primarily found on T and NK cells, thereby suppressing antitumor immunity. Notably, gynecological cancers such as ovarian and endometrial cancers exhibit high expression levels of PVRL2 and PVR, with similar trends observed in various other solid and hematologic tumors. Targeting these immune checkpoint pathways offers a promising therapeutic avenue, potentially in combination with existing treatments. However, the immunomodulatory mechanism involving these bindings, known as the DNAM-1 axis, is complex, underscoring the importance of understanding it for developing novel therapies. This article comprehensively reviews the immunomodulatory mechanisms centered on PVRL2 and PVR, elucidating their implications for various cancer types.
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Inmunoterapia , Nectinas , Neoplasias , Receptores Virales , Humanos , Neoplasias/terapia , Neoplasias/inmunología , Nectinas/metabolismo , Nectinas/inmunología , Inmunoterapia/métodos , Animales , Receptores Virales/inmunología , Receptores Virales/metabolismo , Ligandos , Moléculas de Adhesión Celular/inmunología , Moléculas de Adhesión Celular/metabolismo , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/inmunologíaRESUMEN
Nectin-4 (Nectin cell adhesion molecule 4), a type I transmembrane cell adhesion protein, was demonstrated to be overexpressed in a variety of tumors, making it an attractive antigen for targeted therapies such as antibody-drug conjugates (ADCs). Of great note, the US Food and Drug Administration (FDA)-approval of the first Nectin-4-directed ADC, enfortumab vedotin (EV), in urothelial cancer (UC) not only introduced Nectin-4 as a clinically validated and reliable target antigen but also confirmed the evolving role of Nectin-4-directed ADCs as novel and promising cancer therapeutics. In addition to EV, there have been or are currently being seven and eleven Nectin-4-directed ADCs, respectively, in various stages of clinical trials and preclinical development, offering a promising future for the treatment of Nectin-4-positive cancer patients. This study reviewed clinical- and preclinical-stage Nectin-4-directed ADCs.
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Moléculas de Adhesión Celular , Inmunoconjugados , Humanos , Moléculas de Adhesión Celular/inmunología , Moléculas de Adhesión Celular/metabolismo , Moléculas de Adhesión Celular/antagonistas & inhibidores , Inmunoconjugados/uso terapéutico , Inmunoconjugados/farmacología , Animales , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/farmacología , NectinasRESUMEN
INTRODUCTION: Epithelial ovarian cancer (EOC) is associated with the highest gynecologic cancer mortality. The development of novel, effective combinations of targeted therapeutics remains an unmet medical need. We evaluated the preclinical activity of datopotamab deruxtecan (Dato-Dxd), a novel TROP2 targeting antibody drug conjugate (ADC) in ovarian cancer cell lines and xenografts with variable TROP2 expression. METHODS: In vitro cell viability with Dato-DXd was assessed using flow-cytometry based assays against a panel of EOC primary cell lines with variable TROP2 expression. Fluorescent anti-phospho-histone H2A.X antibody was used to detect dsDNA breaks by flow-cytometry. The in vivo antitumor activity of Dato-DXd was tested in TROP2 overexpressing xenografts. RESULTS: TROP2 overexpressing (3+) and moderate (2+) expressing EOC cell lines demonstrated higher sensitivity to Dato-DXd when compared to TROP2 negative tumors. Dato-DXd exposed TROP2+ EOC demonstrated increased dsDNA breaks and Annexin-V positivity (a marker of apoptosis) when compared to tumor cells exposed to the non-binding conjugate (p = 0.001 and p = 0.016, respectively). Dato-DXd induced significant antibody-dependent cellular cytotoxicity (ADCC) in the presence of peripheral-blood-lymphocytes. While negligible activity was detected against EOC cell lines with low TROP2 expression, Dato-DXd demonstrated significant bystander killing against tumor cells with low/negligible TROP2 when such cells were admixed with TROP2 3+ tumor cells in vitro. Dato-DXd showed tumor growth suppression against EOC cell line derived xenograft models that overexpress TROP2 at 3+ levels, prolonging survival when compared to controls, with minimal toxicity. CONCLUSION: Dato-DXd shows promising preclinical activity against TROP2 overexpressing ovarian cancers. Future clinical trials in ovarian cancer patients are warranted.
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Antígenos de Neoplasias , Carcinoma Epitelial de Ovario , Moléculas de Adhesión Celular , Inmunoconjugados , Neoplasias Ováricas , Ensayos Antitumor por Modelo de Xenoinjerto , Femenino , Humanos , Moléculas de Adhesión Celular/inmunología , Moléculas de Adhesión Celular/metabolismo , Moléculas de Adhesión Celular/antagonistas & inhibidores , Animales , Inmunoconjugados/farmacología , Antígenos de Neoplasias/inmunología , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/metabolismo , Línea Celular Tumoral , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/inmunología , Carcinoma Epitelial de Ovario/patología , Ratones , Ratones Desnudos , Supervivencia Celular/efectos de los fármacosRESUMEN
The approval of Trodelvy® validates TROP2 as a druggable but challenging target for antibody-drug conjugates (ADCs) to treat metastatic triple-negative breast cancer (mTNBC). Here, based on the TROP2-targeted antibody sacituzumab, we designed and developed several site-specific ADC candidates, which employ MMAE (monomethyl auristatin E) as the toxin, via IgG glycoengineering or affinity-directed traceless conjugation. Systematic evaluation of these site-specific ADCs in homogeneity, hydrophilicity, stability, and antitumor efficiency was conducted. The results indicate that the site-specific ADCs gsADC 3b made from one-step glycoengineering exhibit good aggregation stability and in vivo efficacy, providing a new format of ADCs that target TROP2.
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Antígenos de Neoplasias , Antineoplásicos , Moléculas de Adhesión Celular , Diseño de Fármacos , Inmunoconjugados , Humanos , Inmunoconjugados/química , Inmunoconjugados/farmacología , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/metabolismo , Moléculas de Adhesión Celular/antagonistas & inhibidores , Moléculas de Adhesión Celular/metabolismo , Moléculas de Adhesión Celular/inmunología , Animales , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Ratones , Femenino , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Línea Celular Tumoral , Anticuerpos Monoclonales Humanizados/química , Anticuerpos Monoclonales Humanizados/farmacología , OligopéptidosAsunto(s)
Antígenos de Neoplasias , Carcinoma de Pulmón de Células no Pequeñas , Moléculas de Adhesión Celular , Inmunoconjugados , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/inmunología , Inmunoconjugados/uso terapéutico , Antígenos de Neoplasias/inmunología , Moléculas de Adhesión Celular/inmunología , Antineoplásicos Inmunológicos/uso terapéuticoRESUMEN
In arthropods, the involvement of Dscam (Down syndrome cell adhesion molecule) in innate immunity has been extensively demonstrated. Its cytoplasmic tail contains multiple conserved functional sites, which indicates its involvement in different intracellular signaling pathways. In this study, we focused on the role of the cytoplasmic tail of Dscam in the Chinese mitten crab (Eriocheir sinensis) immune defense. In the group with cytoplasmic tail knockdown (the site was located on constant exons 37 and 38), 3885 differentially expressed genes (DEGs) were identified. The DEGs were enriched in small molecule binding, protein-containing complex binding, and immunity-related pathways. The expression of selected genes were validated using quantitative real-time reverse transcription PCR. We identified key Cell cycle, Janus kinase (JAK)-signal transducer, activator of transcription (STAT) and mitogen-activated protein kinase (MAPK) signaling pathway genes, the results indicated that the cytoplasmic tail of Dscam controls antibacterial responses by regulating cell proliferation-related genes in hemocytes.
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Proteínas de Artrópodos , Braquiuros , Hemocitos , Inmunidad Innata , Animales , Braquiuros/genética , Braquiuros/inmunología , Hemocitos/inmunología , Proteínas de Artrópodos/genética , Proteínas de Artrópodos/inmunología , Proteínas de Artrópodos/química , Inmunidad Innata/genética , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Moléculas de Adhesión Celular/inmunología , Regulación de la Expresión Génica/inmunología , Proliferación CelularRESUMEN
OBJECTIVE: Trophoblast Cell Surface Antigen 2 (Trop-2) is a transmembrane glycoprotein that is overexpressed in various cancers, with immunological significance as a target for tumor-reactive T-cells. We aimed to investigate the association between the expression of Trop-2 and the tumor immune microenvironment in cervical cancer. METHODS: The study included 123 patients with cervical cancer who underwent primary surgery between 2000 and 2020 in our hospital. Trop-2 expression was evaluated using anti-Trop-2 monoclonal antibody clone MAB650. Immune biomarkers, including PD-L1 (22C3), CD3 (PS1), and CD8 (4B11), were also evaluated. Trop-2 and PD-L1 positivity were defined by an H-score ≥ 10 and a combined positive score (CPS) ≥1, respectively. Tumor-infiltrating lymphocytes (TILs) were assessed in the five selected independent areas. The correlation between Trop-2 expression and immune biomarkers was analyzed. RESULTS: The cohort comprised patients with squamous cell carcinoma (SCC) (54.5%) and non-SCC (45.5%). Trop-2 was positive in 84.6% of samples and more commonly expressed in SCC (SCC vs. non-SCC; 97.0% vs. 69.6%, p < 0.001). Intratumoral CD3+ and CD8 + TILs were significantly more common in Trop-2-positive cases (CD3, Mann-Whitney U = 383, p < 0.0001; CD8, U = 442, p < 0.0001). Additionally, significant positive correlations were found between the Trop-2 H-score and immune markers (CD3 + TILs, r = 0.295, p < 0.001; CD8 + TILs, r = 0.267, p = 0.001; PD-L1 CPS, r = 0.178, p = 0.025). No significant associations were detected between TILs and other clinicopathological features, including prognosis. CONCLUSION: Expression of Trop-2 in cervical cancer is associated with increased levels of intratumoral TILs, indicating the potential of Trop-2 targeted therapy alone or in combination with immune checkpoint inhibitors.
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Antígenos de Neoplasias , Moléculas de Adhesión Celular , Linfocitos Infiltrantes de Tumor , Microambiente Tumoral , Neoplasias del Cuello Uterino , Humanos , Femenino , Neoplasias del Cuello Uterino/inmunología , Neoplasias del Cuello Uterino/patología , Microambiente Tumoral/inmunología , Moléculas de Adhesión Celular/inmunología , Moléculas de Adhesión Celular/biosíntesis , Persona de Mediana Edad , Antígenos de Neoplasias/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Adulto , Anciano , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Antígeno B7-H1/inmunología , Antígeno B7-H1/biosíntesis , Biomarcadores de Tumor/inmunología , Biomarcadores de Tumor/metabolismoRESUMEN
Background: According to the latest guidelines on chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), patients with CIDP with anti-neurofascin 155 (NF155) antibodies are referred to as autoimmune nodopathy (AN), an autoimmune disorder distinct from CIDP. We aimed to compare the clinical data of patients with AN with anti-NF155 antibodies with those of anti-NF155 antibodies-negative patients with CIDP, and to summarize the clinical characteristics of patients with AN with anti-NF155 antibodies. Methods: Nine patients with AN with anti-NF155 antibodies and 28 serologically negative patients with CIDP were included in this study. Diagnosis was made according to the diagnostic criteria in the European Academy of Neurology (EAN)/Peripheral Nerve Society (PNS) guidelines on CIDP published in 2021. Demographics, clinical manifestations, electrophysiological examination, cerebrospinal fluid (CSF) tests, and response to treatment were retrospectively analyzed. Results: Compared with serologically negative patients with CIDP, those patients with AN with anti-NF155 antibodies were younger (p=0.007), had a younger onset age (p=0.009), more frequent ataxia (p=0.019), higher CSF protein levels (p=0.001), and more frequent axon damage in electrophysiology (p=0.025). The main characteristics of patients with AN with anti-NF155 antibodies include younger age and onset age, limb weakness, sensory disturbance, ataxia, multiple motor-sensory peripheral neuropathies with demyelination and axonal damage on electrophysiological examination, markedly elevated CSF protein levels, and varying degrees of response to immunotherapy. Conclusions: Patients with AN with anti-NF155 antibodies differed from serologically negative patients with CIDP in terms of clinical characteristics. When AN is suspected, testing for antibodies associated with the nodes of Ranvier is essential for early diagnosis and to guide treatment.
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Autoanticuerpos , Moléculas de Adhesión Celular , Factores de Crecimiento Nervioso , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Humanos , Femenino , Masculino , Moléculas de Adhesión Celular/inmunología , Adulto , Persona de Mediana Edad , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Factores de Crecimiento Nervioso/inmunología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/inmunología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Estudios Retrospectivos , Anciano , Adulto JovenRESUMEN
Improved vaccination requires better delivery of antigens and activation of the natural immune response. Here we report a lipid nanoparticle system with the capacity to carry antigens, including mRNA and proteins, which is formed into a virus-like structure by surface decoration with spike proteins, demonstrating application against SARS-CoV-2 variants. The strategy uses S1 protein from Omicron BA.1 on the surface to deliver mRNA of S1 protein from XBB.1. The virus-like particle enables specific augmentation of mRNAs expressed in human respiratory epithelial cells and macrophages via the interaction the surface S1 protein with ACE2 or DC-SIGN receptors. Activation of macrophages and dendritic cells is demonstrated by the same receptor binding. The combination of protein and mRNA increases the antibody response in BALB/c mice compared with mRNA and protein vaccines alone. Our exploration of the mechanism of this robust immunity suggests it might involve cross-presentation to diverse subsets of dendritic cells ranging from activated innate immune signals to adaptive immune signals.
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Vacunas contra la COVID-19 , Células Dendríticas , Ratones Endogámicos BALB C , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Animales , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/química , Humanos , Ratones , SARS-CoV-2/inmunología , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Células Dendríticas/inmunología , COVID-19/prevención & control , COVID-19/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Nanopartículas/química , ARN Mensajero/genética , ARN Mensajero/inmunología , Vacunación/métodos , Vacunas de ARNm/administración & dosificación , Enzima Convertidora de Angiotensina 2/metabolismo , Lectinas Tipo C/inmunología , Receptores de Superficie Celular/inmunología , Receptores de Superficie Celular/metabolismo , Moléculas de Adhesión Celular/inmunología , Femenino , Vacunas de Partículas Similares a Virus/inmunología , Vacunas de Partículas Similares a Virus/administración & dosificación , LiposomasRESUMEN
BACKGROUND: To investigate Ranvier's autoantibodies prevalence and isotypes in various peripheral neuropathy variants, compare clinical features between seronegative and seropositive patients, and elucidate immune mechanisms underlying antibody generation. METHODS: Antibodies against anti-neurofascin-155 (NF155), NF186, contactin-1 (CNTN1), CNTN2, contactin-associated protein 1 (CASPR1), and CASPR2 were identified through cell-based assays. Plasma cytokines were analyzed in anti-NF155 antibody-positive chronic inflammatory demyelinating polyneuropathy (NF155+ CIDP) and Ranvier's antibodies-negative CIDP (Ab- CIDP) patients using a multiplexed fluorescent immunoassay, validated in vitro in a cell culture model. RESULTS: In 368 plasma samples, 50 Ranvier's autoantibodies were found in 45 individuals, primarily in CIDP cases (25 out of 69 patients) and in 10 out of 122 Guillain-Barré syndrome patients. Anti-NF155 and CNTN1-IgG were exclusive to CIDP. Fourteen samples were NF155-IgG, primarily IgG4 subclass, linked to CIDP features including early onset, tremor, sensory disturbance, elevated CSF protein, prolonged motor latency, conduction block, and poor treatment response. NF155-IgG had low sensitivity (20.28%) but high specificity (100%) for CIDP, rising to 88.88% with tremor and prolonged motor latency. Cytokine profiling in NF155+ CIDP revealed distinct immune responses involving helper T cells, toll-like receptor pathways. Some NF155+ CIDP patients had circulating NF155-specific B cells producing NF155-IgG without antigen presence, suggesting therapeutic potential. CONCLUSION: The study emphasizes the high specificity and sensitivity of NF155-IgG for diagnosing CIDP characterized by distinctive features. Further investigation into circulating NF155-specific B cell phenotypes may pave the way for B cell directed therapy.
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Autoanticuerpos , Moléculas de Adhesión Celular , Factores de Crecimiento Nervioso , Fenotipo , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Humanos , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/sangre , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/inmunología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Masculino , Femenino , Moléculas de Adhesión Celular/sangre , Moléculas de Adhesión Celular/inmunología , Factores de Crecimiento Nervioso/inmunología , Factores de Crecimiento Nervioso/sangre , Persona de Mediana Edad , Autoanticuerpos/sangre , Anciano , Adulto , Citocinas/sangre , Nódulos de Ranvier/inmunología , Contactina 1/inmunologíaAsunto(s)
Autoanticuerpos , Moléculas de Adhesión Celular , Kalinina , Penfigoide Benigno de la Membrana Mucosa , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Moléculas de Adhesión Celular/inmunología , Colágeno Tipo XVII , Colágenos no Fibrilares/inmunología , Penfigoide Benigno de la Membrana Mucosa/inmunologíaRESUMEN
Nectin and nectin-like (Necl) co-receptor axis, comprised of receptors DNAM-1, TIGIT, CD96, PVRIG, and nectin/Necl ligands, is gaining prominence in immuno-oncology. Within this axis, the inhibitory receptor PVRIG recognizes Nectin-2 with high affinity, but the underlying molecular basis remains unknown. By determining the crystal structure of PVRIG in complex with Nectin-2, we identified a unique CC' loop in PVRIG, which complements the double-lock-and-key binding mode and contributes to its high affinity for Nectin-2. The association of the corresponding charged residues in the F-strands explains the ligand selectivity of PVRIG toward Nectin-2 but not for Necl-5. Moreover, comprehensive comparisons of the binding capacities between co-receptors and ligands provide innovative insights into the intra-axis immunoregulatory mechanism. Taken together, these findings broaden our understanding of immune recognition and regulation mediated by nectin/Necl co-receptors and provide a rationale for the development of immunotherapeutic strategies targeting the nectin/Necl axis.
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Modelos Moleculares , Nectinas , Unión Proteica , Receptores de Superficie Celular , Humanos , Sitios de Unión , Moléculas de Adhesión Celular/metabolismo , Moléculas de Adhesión Celular/química , Moléculas de Adhesión Celular/inmunología , Cristalografía por Rayos X , Ligandos , Nectinas/metabolismo , Nectinas/química , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/química , Receptores de Superficie Celular/química , Receptores de Superficie Celular/metabolismoRESUMEN
BACKGROUND: Co-signaling and adhesion molecules are important elements for creating immune synapses between T lymphocytes and antigen-presenting cells; they positively or negatively regulate the interaction between a T cell receptor with its cognate antigen, presented by the major histocompatibility complex. OBJECTIVES: We conducted a systematic review on the effects of High Efficacy Disease Modifying Drugs (HEDMDs) for Multiple Sclerosis (MS) on the co-signaling and adhesion molecules that form the immune synapse. METHODS: We searched EMBASE, MEDLINE, and other sources to identify clinical or preclinical reports on the effects of HEDMDs on co-signaling and adhesion molecules that participate in the formation of immune synapses in patients with MS or other autoimmune disorders. We included reports on cladribine tablets, anti- CD20 monoclonal antibodies, S1P modulators, inhibitors of Bruton's Tyrosine Kinase, and natalizumab. RESULTS: In 56 eligible reports among 7340 total publications, limited relevant evidence was uncovered. Not all co-signaling and adhesion molecules have been studied in relation to every HEDMD, with more data being available on the anti-CD20 monoclonal antibodies (that affect CD80, CD86, GITR and TIGIT), cladribine tablets (affecting CD28, CD40, ICAM-1, LFA-1) and the S1P modulators (affecting CD86, ICAM-1 and LFA-1) and less on Natalizumab (affecting CD80, CD86, CD40, LFA-1, VLA-4) and Alemtuzumab (affecting GITR and CTLA-4). CONCLUSION: The puzzle of HEDMD effects on the immune synapse is far from complete. The available evidence suggests that distinguishing differences exist between drugs and are worth pursuing further.
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Esclerosis Múltiple , Animales , Humanos , Moléculas de Adhesión Celular/inmunología , Moléculas de Adhesión Celular/antagonistas & inhibidores , Moléculas de Adhesión Celular/metabolismo , Sinapsis Inmunológicas/efectos de los fármacos , Sinapsis Inmunológicas/inmunología , Sinapsis Inmunológicas/metabolismo , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/inmunologíaRESUMEN
BACKGROUND: CEACAM5 and CEACAM6 are glycosylphosphatidylinositol (GPI)- linked members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family, which are frequently upregulated in epithelial cancers where they contribute to invasion, metastasis, immune evasion, and resistance to anoikis. CT109 is a novel antibody with dual specificity to both CEACAM5 and 6. OBJECTIVES: In this study, we aimed to perform the preclinical characterization of CT109 and antibody- drug conjugate (ADCs) derivatives of CT109, focusing on CT109-SN-38. METHODS: CT109's cognate epitope was characterized by scanning mutagenesis. CT109 specificity and internalization kinetics were assessed by immunoblot and flow cytometry, respectively. Cognate antigen expression prevalence in colorectal cancer and normal tissue arrays was determined by immunohistochemistry. CT109 conjugations were generated by the reaction of reduced CT109 cysteines with maleimide-functionalized payload linkers. In vitro cytotoxic activity of CT109 ADCs was characterized on antigen-positive and negative pancreatic ductal adenocarcinoma cell (PDAC) lines using a luminometric viability assay. In vivo efficacy of CT109-SN-38 was assessed on a PDAC tumor xenograft model at 10 and 25 mg/kg concentrations. RESULTS: CT109 was shown to bind a glycoepitope centered on N309. CT109 is internalized in the CEACAM5+/CEACAM6+ double-positive PDAC line, BxPC-3, with a t1/2 of 2.3 hours. CT109 ADCs elicit a dose and antigen-dependent cytotoxic effect, with CT109-SN-38 exhibiting an IC50 value of 21 nM in BxPC-3 cells. In a BxPC-3 tumor xenograft model, CT109-SN-38 reduced tumor growth and induced regression in 3/10 mice at a concentration 25 mg/kg. CONCLUSION: These data suggest that further preclinical and clinical development of CT109-SN-38 is warranted.
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Antígeno Carcinoembrionario , Moléculas de Adhesión Celular , Proteínas Ligadas a GPI , Neoplasias Pancreáticas , Animales , Femenino , Humanos , Ratones , Antígenos CD/metabolismo , Antígenos CD/inmunología , Antígeno Carcinoembrionario/inmunología , Moléculas de Adhesión Celular/antagonistas & inhibidores , Moléculas de Adhesión Celular/metabolismo , Moléculas de Adhesión Celular/inmunología , Línea Celular Tumoral , Proteínas Ligadas a GPI/metabolismo , Proteínas Ligadas a GPI/antagonistas & inhibidores , Inmunoconjugados/farmacología , Irinotecán/farmacología , Ratones Desnudos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Psoriasis is currently an incurable skin disorder mainly driven by a chronic inflammatory response. We found that subcutaneous application of umbilical cord- derived mesenchymal stem/stromal cells (MSCs) primed by IFN-γ and TNF-α, referred to as MSCs-IT, exhibited remarkable therapeutic efficacy on imiquimod (IMQ)-induced psoriasis-like inflammation in mice. Neutrophil infiltration, a hallmark of psoriasis, was significantly reduced after treatment with MSCs-IT. We further demonstrated that the effects of MSCs-IT were mediated by tumor necrosis factor (TNF) stimulating gene-6 (TSG-6), which was greatly upregulated in MSCs upon IFN-γ and TNF-α stimulation. MSCs transduced with TSG-6 siRNA lost their therapeutic efficacy while recombinant TSG-6 applied alone could also reduce neutrophil infiltration and alleviate the psoriatic lesions. Furthermore, we demonstrated that TSG-6 could inhibit neutrophil recruitment by decreasing the expression of CXCL1, which may be related to the reduced level of STAT1 phosphorylation in the keratinocytes. Thus, blocking neutrophil recruitment by MSCs-IT or TSG-6 has potential for therapeutic application in human psoriasis.
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Células Madre Mesenquimatosas , Neutrófilos , Psoriasis , Animales , Humanos , Ratones , Citocinas , Factores Inmunológicos , Inflamación/genética , Inflamación/inmunología , Células Madre Mesenquimatosas/inmunología , Neutrófilos/inmunología , Psoriasis/genética , Psoriasis/inmunología , Psoriasis/terapia , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/inmunologíaRESUMEN
Inflammation is the body's biological reaction to endogenous and exogenous stimuli. Recent studies have demonstrated several anti-inflammatory properties of Ferula species. In this paper, we decided to study the anti-inflammatory effect of ethanolic extract of Ferula assafoetida oleo-gum-resin (asafoetida) against TNF-α-stimulated human umbilical vein endothelial cells (HUVECs). HUVECs were cultured in a flat-bottom plate and then treated with ethanolic extract of asafoetida (EEA, 0-500 µg/ml) and TNF-α (0-100 ng/ml) for 24 h. We used the MTT test to assess cell survival. In addition, the LC-MS analysis was performed to determine the active substances. HUVECs were pretreated with EEA and then induced by TNF-α. Intracellular reactive oxygen species (ROS) and adhesion of peripheral blood mononuclear cells (PBMCs) to HUVECs were evaluated with DCFH-DA and CFSE fluorescent probes, respectively. Gene expression of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin and surface expression of ICAM-1 protein were measured using real-time PCR and flow cytometry methods, respectively. While TNF-α significantly increased intracellular ROS formation and PBMC adhesion to TNF-α-induced HUVECs, the pretreatment of HUVECs with EEA (125 and 250 µg/ml) significantly reduced the parameters. In addition, EEA pretreatment decreased TNF-α-induced mRNA expression of VCAM-1 and surface protein expression of ICAM-1 in the target cells. Taken together, the results indicated that EEA prevented ROS generation, triggered by TNF-α, and inhibited the expression of VCAM-1 and ICAM-1, leading to reduced PBMC adhesion. These findings suggest that EEA can probably have anti-inflammatory properties.
Asunto(s)
Antiinflamatorios , Moléculas de Adhesión Celular , Ferula , Células Endoteliales de la Vena Umbilical Humana , Extractos Vegetales , Antiinflamatorios/farmacología , Adhesión Celular , Moléculas de Adhesión Celular/biosíntesis , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/inmunología , Selectina E/biosíntesis , Selectina E/genética , Selectina E/inmunología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/inmunología , Humanos , Molécula 1 de Adhesión Intercelular/biosíntesis , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/inmunología , Leucocitos Mononucleares/inmunología , Extractos Vegetales/farmacología , Especies Reactivas de Oxígeno/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/farmacología , Molécula 1 de Adhesión Celular Vascular/biosíntesis , Molécula 1 de Adhesión Celular Vascular/genética , Molécula 1 de Adhesión Celular Vascular/inmunologíaRESUMEN
Naïve T cell activation in secondary lymphoid organs such as lymph nodes (LNs) occurs upon recognition of cognate antigen presented by antigen presenting cells (APCs). T cell activation requires cytoskeleton rearrangement and sustained interactions with APCs. Enabled/vasodilator-stimulated phosphoprotein (Ena/VASP) proteins are a family of cytoskeletal effector proteins responsible for actin polymerization and are frequently found at the leading edge of motile cells. Ena/VASP proteins have been implicated in motility and adhesion in various cell types, but their role in primary T cell interstitial motility and activation has not been explored. Our goal was to determine the contribution of Ena/VASP proteins to T cell-APC interactions, T cell activation, and T cell expansion in vivo. Our results showed that naïve T cells from Ena/VASP-deficient mice have a significant reduction in antigen-specific T cell accumulation following Listeria monocytogenes infection. The kinetics of T cell expansion impairment were further confirmed in Ena/VASP-deficient T cells stimulated via dendritic cell immunization. To investigate the cause of this T cell expansion defect, we analyzed T cell-APC interactions in vivo by two-photon microscopy and observed fewer Ena/VASP-deficient naïve T cells interacting with APCs in LNs during priming. We also determined that Ena/VASP-deficient T cells formed conjugates with significantly less actin polymerization at the T cell-APC synapse, and that these conjugates were less stable than their WT counterparts. Finally, we found that Ena/VASP-deficient T cells have less LFA-1 polarized to the T cell-APC synapse. Thus, we conclude that Ena/VASP proteins contribute to T cell actin remodeling during T cell-APC interactions, which promotes the initiation of stable T cell conjugates during APC scanning. Therefore, Ena/VASP proteins are required for efficient activation and expansion of T cells in vivo.
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Actinas , Linfocitos T CD8-positivos , Moléculas de Adhesión Celular , Proteínas de Microfilamentos , Fosfoproteínas , Linfocitos T , Actinas/inmunología , Actinas/metabolismo , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Moléculas de Adhesión Celular/inmunología , Moléculas de Adhesión Celular/metabolismo , Proteínas del Citoesqueleto , Activación de Linfocitos , Ratones , Proteínas de Microfilamentos/inmunología , Proteínas de Microfilamentos/metabolismo , Fosfoproteínas/inmunología , Fosfoproteínas/metabolismo , Polimerizacion , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
BACKGROUND: Long non-coding RNA small nucleolar RNA host gene 16 (lncRNA SNHG16) is involved in the pathogenesis of acute ischemic stroke (AIS) through the regulation of brain endothelial cell viability, inflammation, atherosclerotic plaque formation, and neural apoptosis. This study aimed to evaluate the prognostic value of lncRNA SNHG16 in AIS patients. METHODS: Newly diagnosed AIS patients (N = 120) were serially recruited. Their lncRNA SNHG16 expressions in peripheral blood mononuclear cells (PBMCs) were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR); serum inflammatory cytokines and adhesion molecules were determined using enzyme-linked immunosorbent assay (ELISA). The accumulating recurrence-free survival (RFS) and overall survival (OS) were analyzed. Moreover, controls (N = 60) were recruited and their lncRNA SNHG16 expressions in PBMCs were detected. RESULTS: LncRNA SNHG16 was declined in AIS patients compared to controls (p < 0.001). Moreover, lncRNA SNHG16 was not related to any comorbidities in AIS patients (all p > 0.05). Interestingly, lncRNA SNHG16 was negatively related to tumor necrosis factor alpha (TNF-α) (p < 0.001), interleukin 6 (IL-6) (p = 0.013), and intracellular cell adhesion molecule-1 (ICAM-1) (p = 0.024), while positively correlated with interleukin 10 (IL-10) (p = 0.022) in AIS patients. Besides, lncRNA SNHG16 was inversely associated with the National Institutes of Health Stroke Scale (NIHSS) score in AIS patients (p = 0.003). During the follow-up period, in 14 (11.7%) patients occurred recurrence and 5 (4.2%) patients died. Unexpectedly, lncRNA SNHG16 was not associated with accumulating RFS (p = 0.103) or OS (p = 0.150) in AIS patients. CONCLUSION: LncRNA SNHG16 relates to lower inflammatory cytokines, adhesion molecules, and milder disease severity, but fails to predict prognosis in AIS patients.
Asunto(s)
Accidente Cerebrovascular Isquémico , ARN Largo no Codificante , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/inmunología , Citocinas/genética , Citocinas/inmunología , Humanos , Inflamación/genética , Inflamación/inmunología , Accidente Cerebrovascular Isquémico/genética , Accidente Cerebrovascular Isquémico/inmunología , Leucocitos Mononucleares/inmunología , MicroARNs/genética , MicroARNs/inmunología , Pronóstico , ARN Largo no Codificante/genética , ARN Largo no Codificante/inmunología , Índice de Severidad de la EnfermedadRESUMEN
Angiosarcoma is a rare, life-threatening soft tissue sarcoma with malignant endothelial cells that is mainly found in the skin. Multidisciplinary approaches are used to treat patients with unresectable metastasized lesions; considering the cellular origin of angiosarcoma, anti-angiogenic therapy has also been used recently. However, these treatments have limited efficacy, and the survival rate remains low. Thus, more effective treatments need to be developed. Nectin cell adhesion molecule 4 (NECTIN4) is highly expressed in malignant tumors and promotes tumor progression. Thus, NECTIN4 is expected to be a novel therapeutic target for cancer. However, the significance of NECTIN4 in angiosarcoma remains unknown. Using immunohistochemistry, we investigated NECTIN4 expression in 74 tissue samples from angiosarcoma patients, finding variable NECTIN4 expression. In addition, we investigated NECTIN4 expression and function in human angiosarcoma cell lines. NECTIN4 expression was higher in angiosarcoma cells than normal endothelial cells, and angiosarcoma cells were sensitive to monomethyl auristatin E, the cytotoxic part of a NECTIN4-targetting antibody-drug conjugate. NECTIN4 knockdown inhibited the proliferation and angiogenesis of angiosarcoma cells, and Src kinase signaling was shown to be involved in NECTIN4 function, at least in part. NECTIN4-targeted therapy has the potential to be a novel treatment strategy for angiosarcoma.